Cartilage is the connective tissue which cushions moveable joints. Joint cartilage damage is commonly referred to by a number of terms which are used interchangeably here, including arthritis, arthroses and osteoarthritis. Osteoarthritis is a syndrome characterized by pathologic change of synovial joints accompanied by clinical signs of pain and disability. Unfortunately, most animals have sustained damage to joint cartilage by middle age. Although the causes of degenerative processes are generally unknown, as a general matter, cartilage damage can be classified as one of two forms of osteoarthritis. Primary osteoarthritis occurs when normal forces act on abnormal cartilage causing degeneration. An example is the aging process, where daily physical activity and cellular metabolism create wear and tear on the articular cartilage leading to an arthritic condition. Secondary osteoarthritis occurs when abnormal forces act on normal cartilage causing degeneration. An example is traumatic injury such as tearing the anterior cruciate ligament which may cause enough damage to the joint capsule to lead to arthritis. The result of primary and secondary osteoarthritis is the same--a painful condition in which the animal typically is caught up in a cycle in which the body cannot efficiently repair itself at a rate faster than the rate of degeneration.
Referring now to FIG. 1, it can be seen that a normal joint 10 constitutes the interface between opposing compact bones 1 and 11. Normal joint 10 includes a fibrous joint capsule 3 which defines a joint cavity 5. Joint cavity 5 is lined with a synovial membrane 4 and is filled with synovial fluid 9. Articular cartridge 6 cushions the contact of bones 1 and 11 in normal joint 10.
Referring now to FIG. 2, it can be seen that an arthritic joint 12 exhibits deterioration of articular cartilage 6' as evidenced by worn, irregular and insufficient thicknesses of articular cartilage 6'. The cushioning of the contact between bones 1' and 11' is thereby diminished, which leads to pain and inflammation in the area. The volume of synovial fluid 9' may also be decreased, further diminishing the cushioning ability of arthritic joint 12.
Many factors affect or exacerbate the extent of cartilage deterioration. For example, some animals are predisposed genetically to joint disease and degeneration of joint tissue at an early age. In addition, an animal's genetic makeup can influence the thickness and durability of cartilage which will affect an animal's predisposition to arthritis. Other animals experience abnormal wear and tear on joints as a result of poor conformation and/or excess mechanical stress on musculoskeletal systems. Also, aggressive exercise schedules during youth (as may occur with race horses or athletes) may accelerate the manifestation of joint deterioration problems in later years.
In any case, once the cartilage of a joint is damaged, an inflammatory response ensues. Inflammation itself may be painful, causing the animal to make musculoskeletal adjustments that can exacerbate the joint damage. In addition, inflammation can reduce circulation to the damaged area, preventing needed nutrients and building materials from reaching the damaged area. The body's attempt to repair the damage can even worsen the injury. Degradative enzymes and histamine released at the site of tissue injuries can cause or worsen an arthritic condition. In addition, it is known that as neutrophils invade the area, free radicals (molecules with an electron shortage) are released into the environment causing oxidative damage. Free radicals released in the joint produce further cellular damage before they can be captured by other electrons from surrounding tissues, for example, from cellular membranes, in order to stabilize themselves, which results in a devastating chain reaction causing further tissue damage and inflammation. If cellular membrane damage becomes extensive, cells may die. Free radicals have also been shown to irreversibly break down cartilage matrix proteoglycans.
Initial attempts at dealing with arthroses involved treatment with non-steriodal anti-inflammatory agents such as aspirin. However, as anatomical and physiological knowledge about cartilage, connective tissue and joints has grown, preferred treatments include dietary supplements for use in rebuilding the damaged connective tissue. In the last two decades, popular treatments have focused on one or another substances, reflecting in part, the growing knowledge about cartilage structure and physiology.
It is now known that cartilage fibers and matrix are initially formed by cells called chondroblasts. After cartilage formation is complete, the mature chondrocytes remain in the matrix to produce cartilage as needed to maintain the cartilage. Hyaluronic acid is an acidic mucopolysaccharide present in the extracellular substance of connective tissue which attracts and holds moisture within the connective tissue and complexes to other amino sugars to form the ground substances of the cartilage matrix.
Glucosamine, an amino sugar, is a major constituent of hyaluronic acid and is preferentially taken up by chondrocytes and used in the synthesis of hyaluronic acid. By increasing the amount of hyaluronic acid, glucosamine supplementation leads to the rehydration of cartilage, resulting in increased lubrication and shock absorbing capability. Glucosamine supplementation also leads to an increase in proteoglycans in the extracellular matrix of articular cartilage, thereby increasing the overall amount and the structural integrity of the cartilage.
Glucosamine is also used by chondrocytes to produce glycosaminoglycans, which lead to the production of proteoglycans that hold and hydrate connective tissue. With glucosamine supplementation, chondrocytes may be able to replenish the cartilage matrix and synovial fluid when cartilage is damaged. This is accomplished, in part, because glucosamine increases production of chondroitin sulfate, a glycosaminoglycan which is a component of joint tissue. In addition, chondroitin sulfate inhibits degradative enzymes. However, due in part to the high molecular weight of chondroitin sulfate, chondroitin sulfate is believed to be broken down in the digestive tract for "re-assembly" into chondroitin sulfate in the joint tissue where needed. The breakdown into smaller pieces is significant because one of these smaller pieces is galactosamine which has been shown to decrease or inhibit chondroitin sulfate synthesis, in comparison to a control group in studies.
Studies have been performed to ascertain the effectiveness of glucosamine as a treatment for arthroses in people, dogs and horses. A common view among veterinarians and medical doctors is that the chondroprotective effect of glucosamine is well supported, with results variable but generally positive, and glucosamine considered generally safe for use in joint disease treatment. Surveys of responses indicated that animals and people treated with glucosamine commonly experience some benefit after two or more weeks of treatment. In humans, substantial benefit was experienced after eight or more weeks of treatment. A survey of veterinarians who utilized a glucosamine product to treat dogs with arthritis concluded the product was helpful for improving mobility and alleviating pain. A study of 25 horses diagnosed with degenerative joint disease showed improvement in horses treated with an oral glucosamine formulation.
However, there appears to be substantial variability in positive response of glucosamine treatments compared to placebo treatment. Three glucosamine treatment studies are summarized below in Table I.
TABLE I Glucosamine Placebo Treatment Time for Treatment % Positive 50% % Positive Data Source Response Response Response Drovanti, et al., "Therapeutic 73% 20 days 41% Activity of Oral Glucosamine Sulphate in Osteoarthritis: A Placebo-Controlled Double- Blind Investigation," Clinical Therapeutics, 3(4):266-72, 1980. Crolle, G., et al., "Glucos- 27% 3 weeks 0% amine Sulphate for Manage- ment of Arthrosis: A Controlled Clinical Investigation," Current Medical Research and Opinion, 7(2):104-109, 1980. Houpt, J., et al., study 49% 8 weeks 45% presented at July 1998--12.sup.th PanAmerican Congress of Rheumatology, Montreal.
While glucosamine does show a benefit, results are clearly variable, from 27% to 49% to 73% positive results. Discounting by subtraction for placebo effects, positive results range from 4% to 27% to 32%.
One available treatment for the protection and repair of connective tissue is based upon a therapeutic composition comprising glucosamine and salts thereof, chondroitin sulfate, and soluble salts of manganese, and is intended to stimulate production of proteoglycans and collagens in animals. The beneficial effects of the glucosamine in this supplement is a cornerstone of this composition, which appears to be formulated on the premise that the rate-limiting step in the production of collagen is the maturation rather than the production of, newly synthesized collagen. While proponents of this therapy acknowledge that steroids, such as corticosterioids and other anti-inflammatory materials such as high doses of aspirin are widely used for the treatment of arthroses, they caution that such drugs may also inhibit the body's own natural healing processes, leading to further deterioration of the connective tissue.
In other treatment protocols, bioflavanols/flavonoids, terms which are variously identified as including polyphenols, proanthocyanidins, aglycons, glycosides and methylated derivatives, commonly extracted from plants, are being used for their free radical scavenging effect. It has been suggested that the use of plant extracts having proanthocyanidin content are useful for fighting the harmful biological effects of free radicals in collagen degradation, alterations of the synovial liquid, and inflammation. In particular, U.S. Pat. No. 5,650,433 to Watanabe, et al., which issued Jul. 22, 1997 and is entitled Chondroprotective Agents, identifies a chondroprotective agent comprising a flavonoid compound having a specified general formula, as well as glycosides thereof. The patent teaches that this compound strongly inhibits proteoglycan depletion from the chondrocyte matrix, functions to protect cartilage, and is extremely effective for the treatment of arthropathy. However, this patent also teaches that conventional analgesic and anti-inflammatory agents are not effective against the destruction of the articular cartilage, and in fact, sometimes exhibit adverse effect in experiments using chondrocytes.
More particularly, the antioxidant, cardiovascular, circulatory and skin treatment uses of bioflavanols have been studied. One clinical in vivo study of dogs demonstrated the effectiveness of bioflavanols from grape seed extract for treating canine hip dysplasia. The study was randomized and double-blinded. Data was collected from 18 dogs from 1 to 13 years of age having clinical and radiographic evidence of bilateral coxofemoral osteroarthritis secondary to hip dysplasia. All dogs were determined to be free of other musculoskeletal problems based upon history, physical exam, blood count and serum biochemistry profile. Brief lameness exams and dog owners' assessments were conducted at 2, 4, 6, 8, 10, 12 and 14 weeks. Data from this study is summarized in Table II below.
TABLE II Bioflavanol Time for Placebo Treatment 50% Treatment % Positive Positive % Positive Data Source Response Response Response Impellizeri, J.A., et al., "14- 85.7% 14 weeks 9.1% Week Clinical Evaluation of an Oral Antioxidant as a Treatment for Osteoarthritis Secondary to Canine Hip Dysplasia," Syosset Animal Hospital, New York, Veterinary Orthopedic Society 24.sup.th Annual Conference, March 1997.
Since cartilage regeneration involves the production of collagen built from the amino acids proline, hydroxyproline, hydroxylysine, and glycine, other known therapeutic approaches to treatment of arthroses teach the use of peptides soluble in cold water, in particular, hydrolyzed collagen. In one study, patients with arthroses were administered peptides having an average molecular weight from 40,000 to 60,000 for an extended period, after which they reported, as a whole, a substantial decrease in pain. The patients were scored for the incidence of various arthritis symptoms such as pain, stiffness, weakness, and sensitivity to weather after the substances were administered for 60 days. Additional test data is summarized below in Table III.
TABLE III Percentage of Test Participants Exhibiting Specified Reduction in Initial Score after Administration of Test Substances Test Substance &lt;25% from 25% to 50% &gt;50% Gelita-Sol D 19% 33% 48% Protein from hen's egg white 77% 13% 10% Gelatin powder 15% 29% 56%
While the treatments discussed above and other therapies are known for the treatment of arthoses, it can be seen that there remains a need for a therapeutic composition which quickly acts to facilitate the repair of connective tissue while concurrently minimizing ongoing degeneration and providing faster relief from the often high levels of joint pain. It is against that background that the advances of the present invention over individual exogenous glucosamine, hydrolyzed collagen, and bioflavanol therapies for the repair of animal connective tissue have been made.
The present invention relates to a new composition and technique for treating osteoarthritis in animals. The preferred embodiment of a composition of the present invention includes exogenous glucosamine, hydrolyzed collagen and a bioflavanol. Preferred glucosamines are glucosamine hydrochloride (HCI) and/or glucosamine sulfate. Preferred bioflavanols are those extracted from grape seeds, pine bark and turmeric root. Proanthocyanidin (also referred to as leucocyanidin or pcynogenol) is most preferred. With horses and larger animals, a preferred treatment method involves application of the composition of the present invention as a top dressing twice a day to the animal's feed. A preferred treatment for humans, dogs and cats involves the ingestion of 1 to 4 tablets or capsules per day of the composition of the present invention.